ABSTRACT How cancer arises from pre-malignant lesions remains largely unknown. Understanding the molecular determinants within pre-malignant lesions that specify the potential for progression towards cancer, and identifying the molecular mechanisms that regulate this transition remain a priority in the fields of cancer prevention and treatment. Senescence is defined as a stable cell cycle exit triggered by stress, ranging from oncogene activation to exposure to genotoxic agents. Recent studies by us and others have indicated that pre- malignant lesions of different origins, including early pancreatic intra-epithelial neoplasia (PanINs) and prostate intraepithelial neoplasia (PINs), contain senescent cells. Importantly, not all cells within pre-neoplastic lesions are senescent, and the molecular characteristics distinguishing senescent cells from their non-senescent counterparts within preneoplastic lesions is unknown. By limiting the proliferation of damaged cells, senescence was first hypothesized to serve as a barrier against cancer progression. Paradoxically, cells within pre-neoplastic lesions are thought to be at the origin of fully malignant cells, thus challenging the stable nature of cellular senescence as a cell cycle exit condition. So far, all studies pertaining to the relationship between senescent preneoplastic lesions and corresponding malignant tumors have relied on correlative assessment of specific traits for each type of lesions. We propose here to characterize and utilize an innovative reporter transgene that allows both the identification and the lineage tracing of senescent cells during tumor progression in vivo. Specifically, our aims are: to identify the molecular bases for senescence in pre-neoplastic lesions (Aim 1); and to determine the fate of senescent cells during cancer progression (Aim 2). Together, these proposed exploratory/developmental studies will inform us of the relationship between cellular senescence and tumor progression in vivo. Along with the current development of senolytic drugs and biologicals, this knowledge could provide new means to prevent cancer progression at stages where it is most efficient.